Bi(OTf)3-catalysed prenylation of electron-rich aryl ethers and phenols with isoprene: a direct route to prenylated derivatives

Electron-rich aryl ethers and phenols react with isoprene (2-methylbuta-1,3-diene) in the presence of catalytic Bi(OTf)(3) at 40 °C to afford the corresponding prenylated or 2,2-dimethylchroman products, respectively, in moderate to good yields. This transformation offers a convenient and expedient entry to prenylated derivatives of electron-rich aromatics that often display enhanced biological activities. The methodology has been employed in the efficient synthesis of a biologically active natural product and related compounds.     

Palladium-catalyzed highly regioselective Heck reaction of aryl nonaflates with electron-rich olefins

Highly efficient palladium-catalyzed Heck coupling of aryl nonaflates with electron-rich vinyl ethers, and enamides is described. These reactions afforded exclusively the branched products in good yields. The results indicated that aryl nonaflates are effective alternative to the frequently employed aryl triflates.     

Mild and efficient nickel-catalyzed Heck reactions with electron-rich olefins

A new efficient protocol for the nickel-catalyzed Heck reaction of aryl triflates with vinyl ethers is presented. Mild reaction conditions that equal those of the corresponding palladium-catalyzed Heck reaction are applied, representing a practical and more sustainable alternative to the conventional regioselective arylation of vinyl ethers. A catalytic system comprised of Ni(COD)(2) and 1,1'-bis(diphenylphosphino)ferrocene (DPPF) in combination with the tertiary amine Cy(2)NMe proved effective in the olefination of a wide range of aryl triflates. Both electron-deficient and electron-rich arenes proved compatible, and the corresponding aryl methyl ketone could be secured after hydrolysis in yields approaching quantitative. Good functional group tolerance was observed matching the characteristics of the analogous Pd-catalyzed Heck reaction. The high levels of catalytic activity were explained by the intermediacy of a cationic nickel(II) complex potentially responsible for the successive β-hydride elimination and base promoted catalyst regeneration. Although these elementary reactions are normally considered challenging, DFT calculations suggested this pathway to be favorable under the applied reaction conditions.     

Heck reactions of 2-substituted enol ethers with aryl bromides catalysed by a tetraphosphine/palladium complex

cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/[PdCl(C₃H₅)]₂ efficiently catalyses the Heck reaction of β-substituted enol ethers with aryl bromides. Employing β-methoxystyrene, 3-ethoxyacrylonitrile or methyl 3-methoxyacrylate, the regioselective α-arylation of these enol ethers was observed in all cases, and mixtures of Z and E isomers were generally obtained, which in many cases yielded a single ketone product after acid treatment. The stereoselectivity of this reaction depends on steric and electronic factors, and better stereoselectivities in favour of Z isomers were observed with electron-rich or sterically congested aryl bromides. Better yields were obtained for this reaction with electron-rich or sterically congested aryl bromides than with electron-poor aryl bromides. This observation suggests that with these β-substituted enol ethers the rate-limiting step of the catalytic cycle is not the oxidative addition of the aryl bromide to the palladium complex.     

Highly regioselective internal heck arylation of hydroxyalkyl vinyl ethers by aryl halides in water

Highly regioselective and fast Pd(0)-catalyzed internal alpha-arylation of ethylene glycol vinyl ether with aryl halides was shown to be possible in water without the need for any halide scavengers or ionic liquid additives. This presents, to our knowledge, the first case of water being utilized in the selective arylation of electron-rich olefins. Resulting alpha-products were hydrolyzed and isolated as corresponding acetophenones in good to excellent yields when using aryl bromides and with good to moderate yields in the case of aryl iodides. Microwave irradiation was shown to be beneficial in activation of aryl chlorides toward the internal Heck arylation. The scope of the protocol was further increased to include different hydroxyalkyl vinyl ethers, these all giving selectively only branched alpha-products. Finally, the active role of the hydroxy group in directing the regioselectivity toward internal arylation of electron-rich olefins, even in nonpolar toluene, was revealed.     

Fast and regioselective Heck couplings with N-acyl-N-vinylamine derivatives

Highly regioselective Heck couplings of aryl triflates with N-acyl-N-vinylamines lacking an N-alkyl substituent were achieved with reaction times of approximately 1 h in yields ranging from 62 to 98% using 1.5 mol % of Pd(2)(dba)(3), 3 mol % of DPPF, and diethylisopropylamine in dioxane. The efficiency of these cross-couplings were studied with several N-vinylamides and an example each of an N-vinylcarbamate and an N-vinylurea. The Heck coupling products easily underwent acidic hydrolysis to the corresponding aryl methyl ketone or in situ hydrogenation in the presence of (Ph(3)P)(3)RhCl under a hydrogen atmosphere to provide the N-acyl derivatives of pharmaceutically relevant benzylic amines. The coupling of a vinyl triflate and more interestingly a vinyl tosylate to N-vinyl acetamide was also studied affording a 2-acylamino-1,3-butadiene with the same high regioselectivity in preference for the alpha-isomer. This result suggests that Heck couplings of electron-rich alkenes with vinyl tosylates also follow a cationic pathway.     

Oxidative cross-coupling of beta,beta-difluoroenol silyl ethers with nucleophiles: a dipole-inversion method to difluoroketones

Oxidative cross-coupling of alpha-aryl-beta,beta-difluoroenol silyl ethers with heteroaromatics in the presence of Cu(OTf)(2) in wet acetonitrile proceeds smoothly, affording heteroaryldifluoromethyl aryl ketones in 61-88% yields. Alcohols also react as nucleophiles under the same conditions to provide alkoxydifluoromethyl aryl ketones in 73-80% yields. [reaction: see text]     

Suzuki-Miyaura cross-coupling of α-phosphoryloxy enol ethers with arylboronic acids

The Suzuki-Miyaura cross-coupling reaction of cyclic ketene acetal phosphates with arylboronic acids was found to be a convenient and highly efficient method for the construction of aryl vinyl ethers. A wide variety of differentially substituted electron-poor and electron-rich arylboronic acids smoothly underwent the coupling process to provide the desired dihydropyrans in moderate to excellent yields.     

Palladium-catalyzed alpha-arylation of esters

A new and simple one-pot procedure for the palladium-catalyzed intermolecular alpha-arylation of esters is described. A number of esters can be functionalized with a wide range of aryl bromides using Pd(OAc)(2) or Pd(2)(dba)(3) and bulky electron-rich o-biphenyl phosphines 1-3. Under the reaction conditions, using LiHMDS as base, alpha-arylation proceeds at room temperature or at 80 degrees C with very good yields and high selectivities for monoarylation. Important nonsteroidal antiinflammatory drug derivatives such as (+/-)-naproxen tert-butyl ester and (+/-)-flurbiprofen tert-butyl ester can be prepared in 79% and 86% yield, respectively. The catalyst system based on the di-tert-butylphosphine (2) is also active for the alpha-arylation of esters using aryl chlorides. Furthermore, using (3) the alpha-arylation of trisubstituted ester enolates can be accomplished to provide compounds that have quaternary centers.     

Site-selective and regioselective Diels–Alder reaction of allenyl aryl ethers

Abstract  

The site-selectivity and regioselectivity of Diels–Alder reactions of allenyl aryl ethers with cyclopentadiene and acrolein were studied. While cyclopentadiene (as an electron-rich diene) only reacted with the external double bond of allenyl aryl ethers to provide the site-selective normal electron demand Diels–Alder cycloadducts, acrolein (as an electron-deficient diene) reacted with the C₁–C₂ π bond of allenyl aryl ethers to provide the site- and regioselective hetero-Diels–Alder cycloadducts as exclusive products.     

Olefin cyclopropanation with aryl diazocompounds upon catalysis by a dirhodium(II) complex

A dirhodium(II) complex with N-perfluorooctylsulfonylprolinate ligands is found to catalyze the cyclopropanation of olefins with simple aryl diazomethanes. In contrast to previously reported dirhodium(II) catalysts, the present complex works well not only with very electron-rich olefins such as enol ethers, but also with styrenes. Consequently, the present catalyst allows to prepare functionalized diarylcyclopropanes in moderate yields with good diastereoselectivity for the cis product, whereas the enantioselectivity of the reaction appears negligible.     

Simple amine/Pd(OAc)(2)-catalyzed suzuki coupling reactions of aryl bromides under mild aerobic conditions

A new palladium catalyst (DAPCy) made from Pd(OAc)(2) and commercially available, inexpensive dicyclohexylamine has been developed for the Suzuki coupling reaction of aryl bromides with boronic acids to give the coupling products in good to high yields. The air-stable catalyst was characterized and well-defined by X-ray crystallography. A catalytic system involving DAPCy in dioxane demonstrates a temperature-dependent reactivity toward aryl bromides with different electronic substituents, and selectively couples electron-deficient aryl bromides with boronic acids over electron-rich ones at room temperature. Another catalytic system employing DAPCy in EtOH provides a general and convenient method to prepare biaryls from aryl bromides and boronic acids with a broad range of functional groups at room temperature and under aerobic conditions.     

Synthesis of di(hetero)aryl sulfides by directly using arylsulfonyl chlorides as a sulfur source

A new, efficient protocol for the synthesis of di(hetero)aryl sulfides is described. Cheap and easily available arylsulfonyl chlorides as a sulfur source reductively couple with electron-rich (hetero)arenes (e.g., indolizines, indoles, electron-rich benzenes, etc.) in the presence of triphenylphosphine to afford di(hetero)aryl thioethers in good yields.     

Regiospecific syntheses of functionalized diaryliodonium tosylates via [hydroxy(tosyloxy)iodo]arenes generated in situ from (diacetoxyiodo)arenes

Ready access to (18)F-labeled aryl synthons is required for preparing novel radiotracers for molecular imaging with positron emission tomography. Diaryliodonium salts react with cyclotron-produced no-carrier-added [(18)F]fluoride ion to produce [(18)F]aryl fluorides. We aimed to prepare functionalized diaryliodonium salts to serve as potential precursors for producing useful (18)F-labeled aryl synthons, such as (18)F-labeled halomethylbenzenes, benzaldehydes, and benzoic acid esters. Such salts were designed to have one functionalized aryl ring, one relatively electron-rich ring, such as 4-methoxyphenyl or 2-thienyl, and a nonfluorine containing weakly nucleophilic anion. Generation of a [hydroxy(tosyloxy)iodo]arene from a functionalized (diacetoxyiodo)arene in situ followed by treatment with an electron-rich arene, such as anisole or thiophene, or with a functionalized arylstannane gave expedient regiospecific access to a wide range of functionally diverse diaryliodonium tosylates in moderate to high yields (44-98%). The described methodology broadens the scope for producing new functionalized diaryliodonium salts for diverse applications.     

Oxidative C-C bond-forming reaction of electron-rich alkylbenzyl ether with trimethylvinyloxysilane

Treatment of an electron-rich benzyl ether with DDQ at ambient temperature followed by addition of a silyl enol ether undergoes a C-C bond-forming reaction to afford 3-alkoxy-3-phenyl-propionyl compound. This is a general reaction and works well with a variety of silyl enol ethers to give carbonyl products in yields ranging from 10 to 85%.     

Alkaline aqueous solution promoted debromination of 1,2 dibromo-fluorocarbons – A convenient method for electron deficient perfluorovinyl ethers

A facile and efficient base-mediated protocol for debromination of vic-dibromides in perfluoroalkyl(aryl) compounds in aqueous medium has been demonstrated. With mild reaction conditions, the developed strategy has a good substrate scope and electron-deficient olefin products were obtained in good yields. A mechanistic explanation of the debromination is offered with three key experimental observations: (1) the reactions are accelerated by the more electron-rich nucleophiles, (2) the reactions are promoted by the more electron poor vic-dibromides in perfluoroalkyl compounds, and (3) the nucleophilic side reaction is preventable. It is evident that the electronic factors strongly dictate vic-dibromides elimination to the perfluorovinyl ethers, which are the precursors for various perfluorinated polymers. The different reaction conditions were tested in implicit solvent (water) conditions, which helped to confirm the E2-like mechanism.     

Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of potassium aryl- and heteroaryltrifluoroborates

An extended study of the reactivity of potassium aryl- and heteroaryltrifluoroborates in Suzuki-Miyaura cross-coupling reactions is presented. The coupling of aryl- and electron-rich heteroaryltrifluoroborates with aryl and activated heteroaryl bromides proceeds readily under ligandless conditions. When deactivated aryl- and heteroaryltrifluoroborates are coupled with aryl and heteroaryl bromides and chlorides, a low loading (0.5-2%) of PdCl(2)(dppf).CH(2)Cl(2) efficiently catalyzes the reactions. Under either condition, reactions can generally be carried out in an open atmosphere.     

Palladium-catalyzed amination of aryl nonaflates

The first detailed study of the palladium-catalyzed amination of aryl nonaflates is reported. Use of ligands 2-4 and 6 allows for the catalytic amination of electron-rich and -neutral aryl nonaflates with both primary and secondary amines. With use of Xantphos 5, the catalytic amination of a variety of functionalized aryl nonaflates resulted in excellent yields of anilines; even 2-carboxymethyl aryl nonaflate is effectively coupled with a primary alkylamine. Moderate yields were obtained when coupling halo-aryl nonaflates with a variety of amines, where in most cases the aryl nonaflate reacted in preference to the aryl halide. Overall, aryl nonaflates are an effective alternative to triflates in palladium-catalyzed C-N bond-forming processes due to their increased stability under the reaction conditions.     

Palladium-catalyzed regioselective Heck arylation of electron-rich olefins in a molecular solvent-ionic liquid cocktail

We have recently established that highly regioselective Heck arylation of electron-rich olefins can be accomplished with aryl halides without using any halide scavengers in imidazolium ionic liquid solvents. The results presented in this paper show that the benchmark electron-rich olefins vinyl ethers can be readily arylated by aryl bromides in a molecular solvent-ionic liquid cocktail with no compromise on regioselectivity. By introducing a small amount of 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF₄]) to DMSO, the arylation reactions of the vinyl ethers 1a-d by the bromides 2a-j took place to afford essentially only the α arylated products. The enamide 1e underwent similar regioselective arylation in the solvent cocktail. In the absence of the ionic liquid, lower regioselectivities were observed. In comparison with the chemistry we have reported so far, the current method reduces considerably the reliance on the volume of ionic liquids used, providing a simpler and more practical synthetic pathway for preparing arylated vinyl ethers and aryl methyl ketones.     

An efficient catalyst for Pd-catalyzed carbonylation of aryl arenesulfonates

Aryl carboxylic esters were synthesized by Pd-catalyzed carbonylation of aryl p-fluorobenzenesulfonates or -tosylates. A unique Josiphos ligand was discovered through high-throughput catalyst screening, which was the key for the successful carbonylation of various substrates. This catalyst is effective and works well for both electron-rich and electron-poor aryl arenesulfonates. Isolated yields of up to 90% were obtained for aryl p-fluorobenzenesulfonates and -tosylates. [reaction: see text]